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Peg-polyacetal and peg-polyacetal-poe graft copolymers and pharmaceutical compositions

A technology of graft copolymer and diol, which is applied in the field of controlled-release pharmaceutical compositions, can solve the problems of graft copolymer systems that do not disclose thermal gel graft copolymers, etc.

Inactive Publication Date: 2008-04-02
AP PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0025] However, there is no disclosure of graft copolymer systems comprising thermogel graft copolymers in which the hydrophobic, bioerodible segment is a polyacetal comprising the units described herein

Method used

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  • Peg-polyacetal and peg-polyacetal-poe graft copolymers and pharmaceutical compositions
  • Peg-polyacetal and peg-polyacetal-poe graft copolymers and pharmaceutical compositions
  • Peg-polyacetal and peg-polyacetal-poe graft copolymers and pharmaceutical compositions

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preparation example Construction

[0479] Preparation of graft copolymers

[0480] Graft copolymers can be prepared by methods known in the art, for example, as in Contemporary Polymer Chemistry, H.R. Allcock and F.W. Lampe, Prentice Hall, Inc. Englewood Cliffs, New Jersey 07632, 1981, and references cited therein described in the literature.

[0481] For example, polyacetal-polyethylene glycol graft copolymers of formula II can be prepared by reaction of divinyl ethers of formula IIa. In a particular aspect of the invention, a particular compound of divinyl ether of formula Ha is either commercially available or prepared by suitable methods known in the art. For example, depending on the identity of variable D, commercially available aminovinyl ethers can be combined with methyl esters to provide divinyl ethers of formula IIa. See US Patent Publication No. 2002 / 0082362 Al, Brocchini et al. Similarly, hydroxy vinyl ether compounds are commercially available and can be used with ester groups in the backbone t...

Embodiment 1

[0569] 9-Fmoc-protected 2-amino-1,3-propanediol (9-fluorenylmethoxycarbonyl-protected serinol) was synthesized by: 2 g (0.022 mol) 2-amino-1 , 3-propanediol (serinol) was dissolved in 54ml of 10% Na 2 CO 3 in solution. 10 ml of dioxane was added and the mixture was stirred in an ice bath. 7.38 g (0.0285 mol) of 9-fluorenylmethyl chloroformate (Fmoc-Cl) was dissolved in 25 ml of dioxane, and added dropwise to the above solution. The reaction mixture was stirred at room temperature for 4 hours. 200 ml of water were added and the product was extracted with ethyl acetate. The ethyl acetate layer was collected and washed with MgSO 4 dry. After filtration and solvent evaporation, the product was reprecipitated from ethyl acetate / hexanes and dried under vacuum.

[0570] PEG-N-succinimide carbonate (PEG-SC) was prepared by dissolving 1 mmol of α-methyl-ω-hydroxy polyethylene glycol (MPEG-OH) in 2 ml of acetonitrile and 0.4 ml of pyrimidine . 2 mmol of N,N'-disuccinimide carbo...

Embodiment 2

[0572] Polyacetal and grafted PEG synthesis was accomplished as follows:

[0573] The first step: the reaction is carried out in a dry box. 1 g (5.09 mmol) of 1,4-cyclohexane dimethylene divinyl ether, 0.5143 g (3.566 mmol) of 1,4-trans cyclohexane dimethylene and 0.4789 g (1.529 mmol) of 9 -Fmoc-protected serinol was dissolved in 6 ml of tetrahydrofuran. 0.34 ml of catalyst, p-toluenesulfonic acid (2% dissolved in tetrahydrofuran) was added by stirring, and the reaction was carried out for 4 hours.

[0574] Step 2: Take out the flask from the dry box and add a few drops of diisopropylethylamine to neutralize the acidic catalyst. The solution was diluted with 19 ml of tetrahydrofuran, and 5 ml of piperidine was added. A deprotection step was performed for 30 minutes, followed by dialysis for 24 hours in tetrahydrofuran (membrane with a molecular weight cut-off of 1000). The solvent was partially evaporated and the concentrated solution was precipitated in methanol. Polyac...

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Abstract

The present invention provides graft copolymer delivery vehicle which comprises a polyethyleneglycol (PEG)-polyacetal (PA) copolymer or a polyethyleneglycol (PEG)-polyacetal (PA)-polyorthoester (POE) copolymer. The polyethyleneglycol-polyacetal graft copolymers or the polyethyleneglycol-polyacetal-polyorthoester graft copolymers, in particular, the PA-g-PEG or the PA-POE-g-PEG suitable for the invention are represented by Formulae (I) and (V).

Description

technical field [0001] The present invention relates to a graft copolymer delivery vehicle consisting of polyethylene glycol-polyacetal and polyethylene glycol-polyacetal-polyorthoester graft copolymer, and a delivery vehicle comprising the A controlled release pharmaceutical composition with an active agent. The graft copolymer delivery vehicle may be a thermogel graft copolymer. The pharmaceutical composition may be in the form of a topical, instillable or injectable formulation for local controlled delivery of the active agent. Background technique [0002] Micellar systems for tumor targeting [0003] One of the major problems in treating cancer is the difficulty of achieving sufficient concentrations of anticancer agents in tumors. This is due to the toxicity of this drug, sometimes extreme, which severely limits the amount that can be used. However, a major discovery of cancer chemotherapy is the so-called EPR (Enhanced Permeability and Retention) effect. The EPR ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08F297/02
CPCC08F287/00C08F261/00A61K47/48784A61K9/0024C08F263/00A61K47/48215C08F283/06A61K47/48192C08L59/00C08L51/006A61K47/34A61K9/0048C08L51/003A61K47/59A61K47/60A61K47/6903C08L2666/02C08G65/00C08G65/26C08G65/48
Inventor 乔治·海勒艾蒂安·沙赫特韦斯卡·顿切瓦
Owner AP PHARMA INC
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